Cutaneous nociceptors lack sensitisation, but reveal \u3bc-opioid receptor-mediated reduction in excitability to mechanical stimulation in neuropathy

Background: Peripheral nerve injuries often trigger a hypersensitivity to tactile stimulation. Behavioural studies demonstrated efficient and side effect-free analgesia mediated by opioid receptors on peripheral sensory neurons. However, mechanistic approaches addressing such opioid properties in painful neuropathies are lacking. Here we investigated whether opioids can directly inhibit primary afferent neuron transmission of mechanical stimuli in neuropathy. We analysed the mechanical thresholds, the firing rates and response latencies of sensory fibres to mechanical stimulation of their cutaneous receptive fields.Results: Two weeks following a chronic constriction injury of the saphenous nerve, mice developed a profound mechanical hypersensitivity in the paw innervated by the damaged nerve. Using an in vitro skin-nerve preparation we found no changes in the mechanical thresholds and latencies of sensory fibres from injured nerves. The firing rates to mechanical stimulation were unchanged or reduced following injury. Importantly, \u3bc-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5]-ol-enkephalin (DAMGO) significantly elevated the mechanical thresholds of nociceptive A\u3b4 and C fibres. Furthermore, DAMGO substantially diminished the mechanically evoked discharges of C nociceptors in injured nerves. These effects were blocked by DAMGO washout and pre-treatment with the selective \u3bc-opioid receptor antagonist Cys2-Tyr3-Orn5-Pen7-amide. DAMGO did not alter the responses of sensory fibres in uninjured nerves.Conclusions: Our findings suggest that behaviourally manifested neuropathy-induced mechanosensitivity does not require a sensitised state of cutaneous nociceptors in damaged nerves. Yet, nerve injury renders nociceptors sensitive to opioids. Prevention of action potential generation or propagation in nociceptors might represent a cellular mechanism underlying peripheral opioid-mediated alleviation of mechanical hypersensitivity in neuropathy. \ua9 2012 Schmidt et al.; licensee BioMed Central Ltd

The contribution of TRPM8 and TRPA1 channels to cold allodynia and neuropathic pain.

Cold allodynia is a common feature of neuropathic pain however the underlying mechanisms of this enhanced sensitivity to cold are not known. Recently the transient receptor potential (TRP) channels TRPM8 and TRPA1 have been identified and proposed to be molecular sensors for cold. Here we have investigated the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG) and examined the cold sensitivity of peripheral sensory neurons in the chronic construction injury (CCI) model of neuropathic pain in mice.In behavioral experiments, chronic constriction injury (CCI) of the sciatic nerve induced a hypersensitivity to both cold and the TRPM8 agonist menthol that developed 2 days post injury and remained stable for at least 2 weeks. Using quantitative RT-PCR and in situ hybridization we examined the expression of TRPM8 and TRPA1 in DRG. Both channels displayed significantly reduced expression levels after injury with no change in their distribution pattern in identified neuronal subpopulations. Furthermore, in calcium imaging experiments, we detected no alterations in the number of cold or menthol responsive neurons in the DRG, or in the functional properties of cold transduction following injury. Intriguingly however, responses to the TRPA1 agonist mustard oil were strongly reduced.Our results indicate that injured sensory neurons do not develop abnormal cold sensitivity after chronic constriction injury and that alterations in the expression of TRPM8 and TRPA1 are unlikely to contribute directly to the pathogenesis of cold allodynia in this neuropathic pain model

Polyglycerol-opioid conjugate produces analgesia devoid of side effects

Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects

ISRM Suggested Method for Laboratory Acoustic Emission Monitoring

Acoustic emission (AE) is defined as high-frequency elastic waves emitted from defects such as small cracks (microcracks) within a material when stressed, typically in the laboratory. AE is a similar phenomenon to microseismicity (MS), as MS is induced by fracture of rock at an engineering scale (e.g., rockbursts in mines), that is, in the field. Thus, seismic monitoring can be applied to a wide variety of rock engineering problems, and AE is a powerful method to investigate processes of rock fracture by detecting microcracks prior to macroscopic failure and by tracking crack propagation. A basic approach involves using a single channel of data acquisition, such as with a digital oscilloscope, and analyzing the number and rate of AE events. Perhaps the most valuable information from AE is the source location, which requires recording the waveform at several sensors and determining arrival times at each. Thus, investing in a multichannel data acquisition system provides the means to monitor dynamics of the fracturing process. The purpose of this suggested method is to describe the experimental setup and devices used to monitor AE in laboratory testing of rock. The instrumentation includes the AE sensor, preamplifier, frequency (noise) filter, main amplifier, AE rate counter, and A/D (analog-to-digital) recorder, to provide fundamental knowledge on material and specimen behavior in laboratory experiments. When considering in situ seismic monitoring, the reader is referred to the relevant ISRM suggested method specifically addressing that topic (Xiao et al. 2016)